chronic lymphocytic leukemia - ematologialasapienza.it · cuellar-garcía et al, eha 2017 oral...

Chronic Lymphocytic Leukemia

Paolo Ghia

Complex Karyotype: a

novel predictive marker?

Thompson PA et al. Cancer 2015

Complex karyotype superseded del(17p)Anderson MA et al. Blood 2017

• ORR in patients treated with IDELA+R with CK was 80.8% (95% CI: 60.6, 93.4) vs 89.7% (95% CI: 75.8, 97.1) without CK

• OS HR for patients treated with IDELA+R with CK vs no CK was 1.97 (95% CI: 0.87, 4.48; p=0.10, unadjusted)

Kreuzer, iwCLL 2017, Presentation #410

Ibrutinib and Idela in

R/R CLL by CK status

PFS and OS by CK statusPFSa

CK IDELA+R (n=26)

CK PBO+R (n=24)

No CK IDELA+R (n=39)

No CK PBO+R (n=38)

CK, complex karyotype; NR, not reached.

Median PFSmo

Del17p + CK (n=22) 25

Del17p no CK (n=10) 52

Jones J, et al. EHA 2016 (Abstract S429; oral presentation).

3580

3179 (89%)

Non-CK

741 (23%)

1 aberration

[non-del(13q)]

406 (13%)

2 aberrations

401 (11%)

CK

2032 (64%)Normal/del(13q)

No difference in the detection rate of CK between different cell stimulation protocols

Dissecting CK in CLL

Baliakas et al, EHA 2017, oral presentation

5 abs vs 4 abs: p<0.055abs vs 3 abs: p<0.054abs vs 3abs: p=ns

Dissecting CK in CLL

52%24%

22%


You need 5 or more

aberrations to be bad

0 5 10 15 20 25

Time (years from diagnosis)

0%

25%

50%

75%

100%%

Aliv

e non CK, n=2856 CK, >= 5 abs, n=80 CK, 4 abs, n=71 CK, 3 abs, n=167

nonCK vs CK 4abs, p=nsnonCK vs CK 3abs, p=ns


Complex karyotype aggravates

outcomes

in IG-unmutated CLL

0 5 10 15 20


0%

25%

50%

75%

100%

% A

live

non CK, n=569 CK, >= 5 abs, n=30 CK, 4 abs, n=28 CK, 3 abs, n=60

p<0.0001


Complex karyotype aggravates

outcomes

in CLL with TP53abs

0 5 10 15


0%

25%

50%

75%

100%%

Aliv

e non CK, n=151 CK, >= 5 abs, n=42 CK, 4 abs, n=17 CK, 3 abs, n=22

5abs vs 4abs vs 3abs: p=ns

p=0.0012


CLL8: Phase 3 randomizedtrial of FCR vs FC in 1L CLL2

0.8

0.6

0.4

0.2

0

1.0

Months on study

PFS

(P

rob

abili

ty)

12 24 36 48 60 960 72 84

p<0.001 FC IGHV-UM (n=195)

FCR IGHV-M (n=113)

FC IGHV-M (n=117)

FCR IGHV-UM (n=197)

Long-term remissions with

FCR in first-line CLL

1. Thompson PA, et al. Blood 2016; 127:303–309;

2. Fischer K, et al. Blood 2016; 127:208–215;

3. Rossi D, et al. Blood 2015; 126:1921–1924.

IGHV-M (n=88)

IGHV-UM (n=126)

p<0.0001

FCR300: Retrospective analysis of300 CLL patients treated with 1L

FCR1

75

50

25

0

100

Time (years)

Pro

gre

ssio

n-f

ree

(%

)

2 4 6 8 10 160 12 14

Low-risk (IGHV-M) (n=90)

High-risk (del(17p)) (n=30)

Intermediate-risk (IGHV-UM and/or del(11q)) (n=197)

60

40

20

0

100

80

Time (months)

Cu

mu

lati

ve p

rob

abili

ty

of

PFS

(%

)

12 24 36 48 60 1200 72 84 96 108

Italian retrospective analysis:404 CLL patients treated with 1L

FCR3

IGHV-M, IGHV-mutated; IGHV-UM, IGHV-unmutated.

Objectives

To evaluate the outcome of M-CLL patients without

poor FISH cytogenetics in relation to the type of

therapy

• 834 CLL patients from 3 European Institutions (Italy,Spain, Sweden)

• M-CLL: n= 493 (165 patients required therapy)

• U-CLL: n= 341 (272 patients required therapy)

Cuellar-García et al, EHA 2017 oral presentation

TFS and OS:mutated vs unmutated CLL

5yr-TFS was 73% (CI, 71-75) for M-CLLand 28% (CI, 26-30) for U-CLL

5-yr OS was 92% (CI, 90-93) for M-CLLand 77% (CI, 75-79) for U-CLL

The median duration of response to first therapy was 28 months (95% CI 24-32 months) in M-CLL vs 18 months (95% CI 16-20) in U-CLL (p<0.001)

n=493 M-CLLMedian 249 (Not evaluable)

n=341 U-CLLMedian 103 (89-117)

P<0.001

Months

OS

Months

n=493 M-CLLMedian 180 (144-217)

n=341 U-CLLMedian 25 (20-29)

P<0.001

TFS


Outcome according to type of therapy in unmutated CLL

n=44 FCR/BR Median 24 (21-33)

n=77 Others Median 21 (14-28)

P=0.811

n=44 FCR/BR median 137 m(117-153)

n=77 Others Median 84 m(75-93)

OS

P=0.003

Months

Patients treated with small molecules and allogeneic SCT were excluded from this analysis

TFS

Months


Outcome according to type of therapy in mutated CLL without

poor cytogenetics

n=21 FCR/BR Median 42 (24-60)

n=53 Others Median 57 (44-69)

P=0.697

TFS OS

n=21 FCR/BR Median 176 (166-185)

Months Months

P=0.468

n=53 Others Median 186(142-217)

Patients treated with small molecules and allogeneic SCT were excluded from this analysis


Phase 2 Study of Ibrutinib, FC, and

Obinutuzumab (iFCG) for Previously Untreated

Patients With CLL With Mutated IGVH and Non-

Del(17p)

Jain et al EHA 2017 oral presentation





Del(17p)




Del(17p)

iFCG induces high rate of MRD- remission in BM (83% after 3

cycles)

All patients (n=9) who reached the 1-year time point were BM

MRD- and have discontinued ibrutinib per study design

Common AEs during iFCG therapy were neutropenia and

thrombocytopenia


Cramer et al EHA 2017 oral presentation

Phase 2 CLL2-Bag Trial of Sequential

Bendamustine (B), Obinutuzumab (G),

and Venetoclax (A) in CLL

Phase 2 CLL2-Bag Trial of Sequential

Bendamustine (B), Obinutuzumab (G),

and Venetoclax (A) in CLL


Authors’ conclusions


Novel drugs

Abstract First author Title

S772 Nastoupil Phase 1 Study of Ublituximab, TGR-1202, and

Ibrutinib in R/R CLL and NHL

S773 Hamlin Phase 2 Study of Cerdulatinib in R/R B Cell

Malignancies

Phase 1 Study of Ublituximab, TGR-

1202, and Ibrutinib in R/R CLL and NHL

Nastoupil et al, EHA 2017 Poster presentation

Phase 2 Study of Cerdulatinib in

R/R B Cell Malignancies:

3 patients at 35 mg BID dose had SAEs

– 2 grade 5 infections, 1 grade 3 pancreatitis

• Starting dose reduced to 30 mg BID and a PK

monitoring and dose reduction strategy was

implemented

Hamlin et al, EHA 2017 Poster presentation

Terminated Phase 2 Study of

Idelalisib and Rituximab in TN CLL

With Del(17p)

Hillmen et al, EHA 2017 oral presentation

• In front-line CLL, IDELA plus rituximab treatment resulted in a similar pattern of AEs to that seen in relapsed CLL studies with similar duration of therapy

– However, the frequency of Grade ≥3 ALT/AST was increased compared to the relapsed setting

• There was no significant effect of age on the risk of either ALT/AST elevations or diarrhoea/colitis

• There was a trend toward higher risk of Grade ≥3 ALT/AST elevation in patients with IGHV mutation

• The occurrence of CMV and PJP infections is consistent with current IDELA labelling and speaks to the potential benefit of risk mitigation through PJP prophylaxis and CMV monitoring during treatment

Authors’ conclusions

Hillmen et al, EHA 2017 oral presentation

THE END

THANK YOU FOR THE ATTENTION

chronic lymphocytic leukemia - ematologialasapienza.it · cuellar-garcía et al, eha 2017 oral...

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